Delta1, 4, 6-pregnatriene-17alpha-ol-3, 20-dione esters



2,962,510 A -PREGNATR1ENE-17cc-()L-3,20-DIONE ESTERS WolfgangHiersemann,

Berlin-Wilmersdorf, tenburg, Germany, Berlin, Germany No Drawing. FiledDec. 9, 1958, Ser. No. 779,048 Claims priority, application Germany Dec.18, 1057 4 Claims. (Cl. 260-3914) Berlin-Halensee, Emanuel Kaspar, andUlrich Kerb, Eeriin-Charlot- This application relates to new steroidderivatives, and more particularly to derivatives of esters of17u-hydroxyprogesterone.

While esters of 17a-hydroxyprogesterone have a greater progestativeaction as well as prolonged activity as compared to progesterone,particularly upon peroral administration, considerable investigation hasbeen and is still being carried out to further increase theprogestativeaction, i.e. to find new derivatives with still greater activity.

It has been discovered that the valuable properties ofl7a-hydroxyprogesterone esters can be improved by introducing anadditional double bond into the 1-position of the ester. This results inincreasing the strength of the action of the compound.

It has furthermore been surprisingly discovered according to the presentinvention that the valuable properties can be still further increased byintroducing a second double bond into the molecule, this second doublebond being in the 6-position. Thus, while esters of Apregnadiene-l7a-ol-3,20-dione have increased activity as compared to thecorresponding ester of l7u-hydroxyprogesterone, it has been discoveredthat the A -pregnatriene-l7ot-ol-3,20-dione esters have still furtherincreased properties.

It is accordingly the primary object of the present invention to providethe new steroid derivatives of the present invention which have improvedprogestative activity as compared to 17a-hydroxyprogesterone and estersthereof.

It is still another object of the present invention to provide for theproduction of the new steroid derivatives of the present invention.

Other objects and advantages of the present invention will be apparentfrom a further reading of the specification and of the appended claims.

With the above objects in view, the present invention mainly comprisesas new compounds, esters of A pregnatrien'e-17u-ol-3,20-dione. Esters ofcarboxylic acids of 1-7 carbon atoms, and particularly of straight chainaliphatic carboxylic acids of 1-7 carbon atoms are most preferred inaccordance with the present invention.

The method of the present invention mainly comprises the introduction ofa carbon-carbon double bond into the l-position and anothercarbon-carbon double bond into the 6-position of esters of17ot-hydroxyprogesterone. In accordance with another embodiment of thepresent invention the two carbon-carbon double bonds are directlyintroduced into 17a-hydroxyprogesterone and the resulting A-pregnatriene-l7a-ol-3,20-dione is then esterified, preferably with analiphatic carboxylic acid of 1-7 carbon atoms.

The advantages of the present invention will be apparent from thefollowing example. While progesterone and 17a-hydroxyprogesterone uponperoral administration have practically no progestative activity, theesteriassignors to Firma Schering A..G.,

Patented Nov. 29, 1960,

'pregnatriene-l7a-ol-3,20-dione-esters of aliphatic carboxylic acids ofpreferably 1-7 carbon atoms is entirely analogous. The new valuableesters of A -pregnatrienel7a-ol-3,20-dione can be produced according tomethods known in steroid chemistry, particularly by brominating thecorresponding l7ot-hydroxyprogesterone ester with two mols of bromineand subsequently splitting oif of two mols of hydrogen bromide. Thebromination is preferably carried out in absolute dioxane utilizingbromine which has been previously distilled over phosphorus pentoxide,at room temperature. A bromination is advantageously carried out underreduced pressure, for example, about 300 mm. Hg, in a stream of nitrogento promote the removal of the formed hydrogen bromide. The subsequentsplitting off of the hydrogen bromide from the formed dibromide compoundis preferably carried out by cooking the crude brominated product with atertiary base, preferably collidine.

The following examples are given to further illustrate the. presentinvention. The scope of the invention is not, however, meant to belimited to the specific details of the examples.

Example 1 12.5 g. of 17a-hydroxyprogesterone-17-acetate are suspended in400 cc. of absolute dioxane. 3.7 cc. of bromine previously distilledover phosphorus pentoxide are added at room temperature under stirringand While conducting a dry nitrogen stream therein. The reaction mixtureis stirred for hour at this temperature under a pressure of 300 mm. Hgand while passing a mild stream of nitrogen therethrough. The reactionmixture is then introduced dropwise into ice Water while stirring, thethus formed precipitate is filtered off by suction, washed untilneutral, and dried under vacuum at -9 C. There is thus obtained a 17.8g. of 2,6-dibromo-l7a-hydroxyprogesterone-l7-acetate having a meltingpoint of 138 C. (with decomposition). The decomposition melting point isdetermined according to the method of Bohme, Deutsche Apothekerzeitung95, 153 (1955).

Recrystallization from 1:1 methylene chloride/methanol results inincrease of the melting point to 142 C. (with decomposition). Thedibromide absorbs in ultraviolet at 250 mg with an extinction at 12300.

14.2 g. of the crude dibromide compound are cooked under refluxing whilestirring in a nitrogen atmosphere for 5 hours with 500 cc. of freshlydistilled collidine. After cooling a mixture of dilute hydrochloric acidand ice (approximately 2 N are added dropwise under stirring to thereaction mixture. The reaction mixture is then extracted with ether,subsequently washed first with 2 N hydrochloric acid and then with wateruntil neutral, dried, and then the ether is distilled off under vacuumat 30 C. The remaining yellow-brown foamy residue (8.7 g.) is taken upin 1:1 carbon tetrachloride/methylene chloride, and eluated with 1:2carbon tetrachloride/ methylene chloride over 450 g. of aluminum oxide(Woelm, acid). After recrystallization, the resulting substance is theweakly straw-yellow 17ot-hydroxy-A -pregnatriene-3,20-dione-17-acetatehaving a melting point of 192-492.? C. The triene absorbs in ultravioletat the following wave lengths (in methanol) with the extinctions setforth below:

E =11,025 E259: E =12,830 Example 2 i 12.5 g. of17a-hydroxyprogesterone-17-caproate are brominated as described inExample 1.

Two fractions are obtained by cr ystallization of the crude product(16.5 g.) from methylenechloride/methan- 01:

2.678 g. 2,6B-dibromo-17bt-hydroxypi-ogesterone 17aoaproate meltingpoint=113/11 4 11"6 C. (with decomposition). I

Ultraviolet absorption at E =12,340 (methanol).

3.13 g. 2,6a-dibro mo-17oL-hydroxyprogestrone-17mcaproate meltingpoint'=165166 C. (with decomposition).

Ultraviolet absorption at 15 5 12100. I

The 6fi-bromide moves the ultraviolet Spectrum 10 m into the longer wavelength While the Set-bromide is without influence on the absorption ofM-S-keto-compounds. (C. Djerassi et al., Am. Soc. 72, 4534 (1959).)

V 6.9 g. of the above dibromide compound is introduced into 1.4 Iitersof ice-cooled 2 N hydrofluoric acid under stirring. It is subsequentlyextracted with ether, washed with water'until neutral, dried, and thesolvent is distilled off. The yellowish-brown resldue (4.6 g.) isextracted with 1:1 carbon tetrachloride/ methylene chloride and eluatedover 600 g. of aluminum oxide (Woelm, approximately neutral, 1% H O)with 1:2 carbon tetrachloride/ methylene chloride.

After recrystallization from ether/pentane, the colorless 17a hydroxyA?' -pregnatriene-3,20-dione-17-cap-roate having a melting point of1'00/101 103 C. (4lmin.) is obtained.

The trienone exhibits the following ultraviolet absorptions:

Ezos=14,150 E255 E220=12,700 v E300=12,32O

(methanol) The splitting oil of hydrogen bromide from the dibromide,melting point equal 165-166 C., results in the formation of the A-3-keto-systern. Both reaction products have the same melting point,analysis, ultra-violet and infra-red spectrums.

Example 3 1 g. of 17a-hydroxyprogesterone and 3 g. of chloranil arecooked under refluxing in 150 cc. of n-amyl alcohol for 4 hours whilepassing a stream of nitrogen therethrough (compare Agnello and Laubach,Journ. Amer. Chem. Soc., vol. 72, page 1257 (1957) T he amyl alcohol isdistilled off under vacuum, the residue taken up in methylene chloride,and the solution washed three times with Weak alkaline sodium dithionitesolution, two times with n/ 10 sodium hydroxide and subsequently withwater until neutral. After drying and distilling off of the solvent thebrown residue is dissolved in methanol, cooked with activated carbon,subjected to suction filtration, and concentrated. There is thusobtained 0.4053 g. of crude l7a-hydroxy-A -pregnatrienefi,20 dionehaving a melting point of 220-237 C. After several recrystallizationsfrom methanol, the melting point E203=12,68O Egg 1 E 11,990 E 12,940

0.328 g. of A --17a-hydroxyprogesterone, 0.172 g. of p-toluene-sulfonicacid and 15 cc. of acetanhydride are stirred for 1 /2 hours under theintroduction of nitrogen at room temperature.

For further working up, the reaction mixture is poured into 200 cc. ofice water and 10 cc. of pyridine, extracted with methylene chloride,the'organic phase washed until neutral with water, dried, and thesolvent evaporated. The yellow oily residue is chromatographicallyextracted on aluminum oxide (Woelm, acid, 1% H O). The A17a-hydroxyprogesterone-17-acetate is eluated with 2:1 methylenechloride/ carbon tetrachloride, and then recrystallized from methanol.

Melting point: l-97198 C. (u) 2 +31.4 (CHCl Example 4 1 g. of17e-hydroxy progesterone-formate and 3.5 g. of chloranil are cooked in300 cc. of n-amyl alcohol for 4 hours under refluxing while introducingnitrogen therein.

The amyl alcohol is distilled off under vacuum, the residue dissolved inmethylene chloride and the solution washed withweak alkaline sodiumdithionite solution with n/ 10 sodium hydroxide and subsequently withwater until neutral. After distilling 01f the. solvent, the residue isdissolved in 1:1 methylene chloride/ carbon tetrachloride and extractedon a column of aluminum oxide (Woelm, neutral, 1% H 0), The A-17a-hydroxypr'ogesterone-l7-formate is eluated with 2:1 methylenechloride/ carbon tetrachloride.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this inventionand, therefore, such adaptations should and are intended to becomprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be secured by Letters Patent is: I

1. 17 esters of A pregnatriene-17a-ol-3,20-dione with aliphaticcarboxylic acids of 1-7 carbon atoms.

2. 17oz hydroxy-A -pregnatriene-3,20dionc-17-acetate.

3. 17a hydroxy-A -pregnatriene-fa',20-dione-l7-caproate.

4. A -17a-hydroxy-progesterone-l7-forrnate.

References Cited in the file of this patent

1. 17 - ESTERS OF $1,4,6 - PREGNATRIENE-17A-OL-3,20-DIONE WITH ALIPHATICCARBOXYLIC ACIDS OF 1-7 CARBON ATOMS.